Penicillin V prophylaxis uptake among children living with sickle cell disease in a specialist sickle cell clinic in Ghana: A cross‐sectional study

Abstract Background and Aims Penicillin V prophylaxis protects children living with sickle cell disease (SCD) from bacteria infections especially Streptococcus pneumonia. However, the uptake of penicillin V prophylaxis is difficult to assess and often poor among SCD patients. Therefore, this study sought to investigate oral penicillin V prophylaxis adherence among SCD children using urine assay and self‐reported methods and the associated factors. Methods The study employed an analytical cross‐sectional design in the assessment of penicillin V prophylaxis adherence using both urine assay and self‐reported methods. Multiple logistic regression analysis was used to determine the factors associated with penicillin V prophylaxis adherence. A p value < 0.05 was considered statistically significant. Results Among the 421 SCD patients recruited, penicillin V prophylaxis adherence was observed to be 30.0% and 68.0% for the objective and subjective methods of assessment, respectively. For the objective method of assessment, being cared for by grandparents increased the odds of penicillin V adherence (adjusted odds ratio [aOR] = 3.68, confidence interval [CI] = 1.03–13.15). However, SCD patients within the ages of 10–14 years (aOR = 0.36, CI = 0.17–0.80), >14 years (aOR = 0.17, CI = 0.05–0.61), SCD patient cared for by married caregivers/parents (aOR = 0.32, CI = 0.14–0.72), SCD patient cared for by divorced caregivers/parents (aOR = 0.23, CI = 0.07–0.75), SCD patients taking homemade (herbal) preparations for the treatment of SCD (aOR = 0.42, CI = 0.21–0.83), and inappropriate intake of penicillin V prophylaxis (aOR = 0.27, CI = 0.11–0.67) reduced the odds of penicillin V adherence. For the subjective method of assessment, taking homemade preparation (herbal) for the treatment of SCD (aOR = 0.52, CI = 0.30–0.89) and inappropriate intake of penicillin V (aOR = 0.32, CI = 0.17–0.60) reduced the odds of penicillin V adherence. Conclusion This study reports a relatively low adherence rate of penicillin V prophylaxis among children living with SCD. Educating and counseling both SCD patients and/or caregivers on the need to be adherent to penicillin V prophylaxis could prevent complications that may arise from nonadherence.


| BACKGROUND
Sickle cell disease (SCD) is the most common inherited disorder among hemoglobinopathies and is designated a global health problem. 1,2 SCD is a recessively inherited disorder predominantly distributed with descent from African, Middle Eastern, Mediterranean, Indian, South and Central American, and Asian populations.
Annually, over 300,000 children are born with this disorder globally and this number is expected to increase to 400,000 by 2050. 3,4 In sub-Saharan Africa, about 8 in 10 children are born of SCD which is reported to be associated with a high mortality rate in such children. 5,6 In Ghana about 2 out of 100 newborns are diagnosed as having SCD with approximately 6 in 10 having the homozygous form (SS). 7 The current daily treatment regimen such as folic acid, hematinics, penicillin V and hydroxyurea has significantly improved the health outcomes of SCD patients as well as reduced the mortality rate of the disease. In sub-Saharan Africa, infection alone contributes to about 50.0% mortality rate among children (under 5) diagnosed with SCD. [8][9][10] Penicillin V protects SCD patients from bacteria infections including Streptococcus pneumonia. 11,12 It has been reported that oral penicillin V prophylaxis reduces 84% pneumococcal infections and related deaths when given twice daily. 13 Nonetheless, without penicillin V treatment, infection predisposed SCD patients to other events such as acute chest syndrome (ACS), pain, sequestration, and hyperhemolytic episodes. 14 Although the life expectancy of SCD patients has improved in recent times, the current medication regimen is a major barrier to medication adherence. Medication adherence is a complex problem that involves the patient, caregiver, and healthcare practitioner. 15 Adherence is defined as the extent to which patients' actions coincide with the agreement of recommendations by healthcare providers. 16 Medication adherence among children suffering from chronic conditions is problematic. 17 Averagely about 50% of children with chronic conditions are adherent to medication with wide varying levels ranging from 11% to 93% 18 which decreases with increasing age to about 5% to 15%. 17 Given the benefits of penicillin V prophylaxis in reducing infection-related complications in SCD patients, it is imperative to effectively monitor penicillin V adherence among SCD patients. However, the existing body of literature on penicillin V adherence among SCD patients is limited and not contemporary to inform policies for present issues. [19][20][21] A literature search suggested that in Ghana and sub-Saharan Africa, the level of adherence to penicillin V prophylaxis and factors influencing adherence has not been well studied and, therefore, called for an investigation.
The current study assumed that adherence to penicillin V medication is poor among SCD children and this is because children are vulnerable and their medication adherence is significantly influenced by their parents. The present study, therefore, sought to determine oral penicillin V prophylaxis adherence among SCD children and the associated factors. To the best of our knowledge, this is the first study assessing the adherence to penicillin V prophylaxis among children living with SCD in Ghana using both self-reported and urine assay methods of assessment. The findings from this study will provide an empirical understanding on how children with SCD in Ghana take oral penicillin V prophylaxis.

| Study design
The study employed an analytical cross-sectional design that involved both quantitative data collection techniques and laboratory analysis of urine samples of SCD children who presented at the outpatient clinic from October 1, 2021, to January 31, 2022.

| Study area
The study was conducted at Komfo Anokye Teaching Hospital (KATH), Paediatric SCD Clinic. KATH is located in the Kumasi metropolis, the regional capital of the Ashanti Region. The Ashanti Region is the second largest of the 16 administrative regions of Ghana with a population of 5.4 million. 22 Due to its central location in Ghana, it is accessible from all corners of the country. 23 KATH is a tertiary hospital with a bed capacity of 1200 and serves as a major referral center for the middle and northern zones of Ghana. 24 The Child Health Directorate of KATH runs a 24-h specialist outpatient clinic and six in-patient wards. The SCD outpatient clinic is one of the specialist clinics organized by the directorate and runs 4 days a week and its being run by four specialist pediatricians, three resident's doctors, and six nurses. Averagely, the clinic sees about 500 SCD patients monthly. Based on the standard operating procedure for the management of SCD at the clinic, SCD patients below 3 years and those 3 years and above are scheduled for a visit every 2 and 3 months, respectively. Also, routine laboratory tests such as complete blood counts with reticulocyte counts, kidney function test, liver function test, and eye examination are done. 25 In terms of routine regimen, SCD patients are given folic acid, hematinic, hydroxyurea (SS genotype and some SC genotype with severe form of crisis), and penicillin V (being prescribed to all age groups).

| Study population
Children between 2 and 17 years diagnosed with SCD who were in steady-state (Steady state was defined as any SCD patients free from infection, painful episodes or other disease processes) and registered into the Kumasi Sickle Pan African Research Consortium (SPARCo) registry were included in the study. However, SCD patients who had consumed any other antibiotics 72 h before recruitment and had sought healthcare at the clinic for less than 12 months were excluded.

| Sample size estimation
The sample size was calculated using Cochran's prevalence formulae. 26 A previous study conducted in New York at Children's Hospital of Buffalo, reported penicillin V adherence level of 43.1%. 27 Using a 95% confidence interval, 5% error margin and accounting for a nonresponse of 10%, a minimum sample size of 410 was estimated.

| Sampling techniques
Simple random sampling was employed to recruit the estimated sample from the SCD patients from the SPARCo-Kumasi Registry. 28 With ethical approval, the SCD patients within the stated age categories were sampled from the registry using the research randomizer online 29 taking into consideration the study sample size.
The sampled patients were contacted during their clinic visit at the paediatric sickle cell clinic at KATH. Instances where sampled patients were excluded, resampling was done to replace the excluded patients until achieving the required sample size (Figure 1).

| Study procedure
The sampled SCD patients were screened for eligibility. Consent was obtained from parents or legal guardians of all patients with assent obtained from patients 7 years and above. Urine sample containers were given to the patients to provide a urine sample. The procedure for the collection of the urine sample was explained and demonstrated to the patients and/or the caregivers to provide a 5 ml clean catch urine. 30 The samples were refrigerated at 4°C immediately upon receipt. A 30 min questionnaire was then administered by the research assistants to the caregiver and study participant. The urine sample was then sent to the laboratory for the detection of penicillin V in the urine.

| Micrococcus luteus method for detection of penicillin V in patient urine sample
According to Groove and Randall, penicillin V can be detected in urine as low as 0.005 unit/mm and also be detectable 16 h after last dose of consumption. 31 The indicator organism for the detection of the penicillin V was M. luteus. M. luteus is a member of the family Micrococcaceae and is usually regarded as contaminants from skin and mucus membrane which forms yellowish colonies and appears as a gram-positive coccus typically arranged in tetrads. 32 The following technique was used in the detection of penicillin V in the urine sample of SCD patients.

| DATA COLLECTION METHODS AND INSTRUMENT
The tool for the study was pilot-tested at the Kwame Nkrumah University of Science and Technology noncommunicable disease clinic (the clinic also sees paediatric SCD patients) and Maternal and Child Health Hospital, all in Kumasi. Forty-one participants, making 10% of the calculated sample size was used for the pilot test, to accomplish a reasonable power to ensure the reliability and validity of the questionnaire. For consistency, the questionnaire was translated into the local language (Asante Twi). The structured questionnaire was answered by the SCD patients and/or caregivers (the questionnaire was answered by SCD patients (≥8 years) and their caregivers, and for SCD patients below 8 years, their caregivers answered the questionnaire on their behalf). The study instrument consisted of background characteristics of caregivers and patients, clinical history, and barriers to penicillin V consumption. These data were collected using an electronic version of the questionnaire designed with Research Electronic Data Capture (REDCap). 33 These data were routinely reviewed to ensure completeness and accuracy.

| MEASUREMENT AND STATISTICAL ANALYSIS
The outcome variable, "penicillin V adherence" was measured in two forms, the urine assay (objective) method being the primary outcome variable and the self-reported (subjective) being the secondary outcome variable. The primary outcome variable was measured as binary "adherent" and "nonadherent." Indication of any evidence of any zone of inhibition of the M. luteus on the agar plate was termed as "adherent" and "nonadherent" indicated its absence.
Self-reported adherence was measured by asking the patient or caregiver who reported taking at least one dose of penicillin V within 15 h of recruitment. Patients who reported to have consumed penicillin V within 15 h were deemed "adherent" and above 15 h were considered "nonadherent." Patients who had consumed penicillin V within 15 h are more likely to have penicillin V present in their urine since penicillin V can still be detectable 16 h after the last dose. 34 Adherent and nonadherent were coded as 1 and 0, respectively.

| Independent/predictor variables
The predictor variables that were measured in this study were background characteristics of SCD patients and caregivers, clinical history of SCD patients, and barriers to penicillin V adherence (the responses to the barriers to adherence were "Yes" and "No." Scores were generated for each "Yes" (1) and "No" (0) response). Intake of penicillin V was categorized as inappropriate or appropriate.
Inappropriate intake was defined as SCD patients who underutilized (underuse) and/or overutilized (overuse) penicillin V medication respective of age.

| Statistical analysis
Data cleaning and analysis were done using Stata (STATA/SE version 17.0). Descriptive statistics were performed for all variables and expressed as mean and standard deviation for continuous variables.
Categorical variables were expressed as proportions and presented using tables and charts. χ 2 test of association was used to compare the objective and subjective assessments.  Most primary caregivers 377 (89.55%) were the biological parents of the patients (Table 1).

| DISCUSSION
Medication adherence in chronic disease patients is recognized as a public health problem. This is because nonadherence to medications can result in increased healthcare costs and poor health outcomes. 35 This study used self-reported penicillin V adherence and urine assay of penicillin V as a proxy for penicillin V adherence, and it was shown that self-reported penicillin V adherence was higher than adherence by urinary assay. Further, there was a significant difference between the two methods. We anticipate that the disparities in penicillin V adherence between the two methods could be attributed to recall bias in reporting self-adherence.    Ghana). On the other hand, medication adherence for infant's/ toddlers is determined largely by the parents/caregiver, hence such patients are most likely to administer the medication efficiently thereby enjoying the benefits associated with penicillin V prophylaxis.
Another reason could be due to healthcare providers in the clinic may stress on adherence to penicillin V among children under 5 due to the high susceptible rate of infection-related admission and complications. 19 Also, other factors such as an individual's cognitive level, physical mobility, and self-care abilities may also have an impact on age and adherence to medication. It is therefore important that education at the SCD clinics is heightened.
Marital status of caregiver significantly influences medication adherence levels. Our study showed that SCD children in the care of married caregivers poorly adhere to penicillin V prophylaxis than those whose caregivers are unmarried. These findings contradict the outcome of several studies. [42][43][44]  Social support intervention is recommended for widowed caregivers due to the evidence of its effectiveness in improving medication adherence as reported in some studies. [45][46][47] In this present study, being cared for by grandparents was associated with a high level of adherence to penicillin V prophylaxis.
Globally, grandparents play vital roles in the lives of their beloved young grandchildren. In many families, they serve as primary caregivers to their grandchildren. All the grandparents who cared for the SCD patients seen during the study were above 50 years.
Evidence suggests that among adults, increasing age is associated with medication adherence. [48][49][50] That is, the more one lives with a condition the more likely the person develops knowledge and awareness of the condition. Since the grandparents serve as primary caregiver for their grandchildren, they will ensure their grandchildren

| LIMITATION
The present study has some limitations. First, patients recruited were sampled from the SPARCo registry and accessed care at the KATH SCD clinic. It, therefore, excludes SCD patients less than 2 years and also patients accessing care at other peripheral hospitals in Kumasi and other regions of Ghana. Second, this study was a cross-sectional study where penicillin V adherence for the objective method (urine assay method) was assessed at a one-time-point. There is a need for future studies to assess penicillin V adherence longitudinally. Finally, the subjective nature of self-reported adherence could introduce recall bias and hence may not give a true picture of penicillin V adherence. However, the study provides empirical evidence on adherence to penicillin V prophylaxis.

| CONCLUSION
The study revealed a significant difference between the objective and subjective methods of assessment of penicillin V prophylaxis adherence. Overall, penicillin V prophylaxis adherence was relatively poor among the children with SCD in this study. Age of SCD patients, marital status of caregiver, taking of homemade medications for SCD treatment and inappropriate intake of penicillin V prophylaxis accounted for poor adherence to penicillin V prophylaxis. However, SCD children being cared for by a grandparent as primary caregiver were more adherent to penicillin V prophylaxis. The poor adherence to penicillin V prophylaxis among SCD patients is a public health concern. Therefore, it is imperative to intensify education and counseling for patients and/ or caregivers about the detrimental effects of poor adherence to penicillin V prophylaxis, and adherence should be a collective responsibility of patients and caregivers.